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Keywords:

  • prostate cancer;
  • inflammation;
  • NF-κB;
  • IKK-α;
  • metastasis;
  • apoptosis;
  • castration-resistant

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References
  • Inflammation is involved in regulation of cellular events in prostate carcinogenesis through control of the tumour micro-environment. A variety of bone marrow-derived cells, including CD4+ lymphocytes, macrophages and myeloid-derived suppressor cells, are integral components of the tumour micro-environment.
  • On activation by inflammatory cytokines, NF-κB complexes are capable of promoting tumour cell survival through anti-apoptotic signalling in prostate cancer (PCa). Positive feedback loops are able to maintain NF-κB activation.
  • NF-κB activation is also associated with the metastatic phenotype and PCa progression to castration-resistant prostate cancer (CRPC).
  • A novel role for inhibitor of NF-κB kinase (IKK)-α in NF-κB-independent PCa progression to metastasis and CRPC has recently been uncovered, providing a new mechanistic link between inflammation and PCa. Expansion of PCa progenitors by IKK-α may be involved in this process.
  • In this review, we offer the latest evidence regarding the role of the NF-κB pathway in PCa and discuss therapeutic attempts to target the NF-κB pathways. We point out the need to further dissect inflammatory pathways in PCa in order to develop appropriate preventive measures and design novel therapeutic strategies.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

More than 150 years after renowned pathologist Rudolf Virchow proposed that cancer originated at sites of chronic inflammation [1], the paradigm that accounts for the impact of chronic inflammatory processes in the tumour micro-environment on the six hallmarks of cancer has been widely accepted [2]. Cancer-associated inflammation is marked by the presence of inflammatory cells and chemical mediators including cytokines, chemokines, reactive oxygen species and prostaglandins [3]. Activation of the inflammatory response is able to favour tumour initiation and progression through DNA damage, alteration of microRNA expression levels, promotion of cell proliferation, inhibition of cell apoptosis, stimulation of angiogenesis and modulation of migration and adhesion processes [3].

Similarly, a substantial body of evidence has now confirmed the link between chronic inflammation and prostate cancer (PCa) [4]. Early epidemiological studies reporting an association between prostatitis and PCa are difficult to interpret because those studies might have been influenced by detection and recall bias. Nevertheless, inflammatory infiltrates are found in the majority of PCa specimens, albeit to varying degrees. Specifically, a variety of bone marrow-derived cells, including CD4+ lymphocytes, macrophages and myeloid-derived suppressor cells, are important components of the tumour micro-environment [5, 6]. Although the adaptive immune system is believed to mediate antitumour effects through immunosurveillance, it seems that many tumours acquire the ability to subvert inflammatory signals to their benefit. In this context, the master transcription factor NF-κB has been recognized as the major effector of pro-inflammatory processes involved in PCa pathogenesis. NF-κB activation occurs not only in inflammatory cells, but also in cancer cells, as we discuss in the present review. This review is focused on the current knowledge of the contribution of NF-κB to PCa pathogenesis. We present experimental and clinical evidence that NF-κB is involved in anti-apoptotic and growth-promoting cell signalling, promotion of invasive and metastatic properties and resistance to chemotherapy and radiation in PCa. Special consideration will be given to the latest insights regarding novel mechanisms involving inhibitor of NF-κB (IκB) kinase (IKK)-α function in PCa. Finally, we discuss therapeutic attempts to target NF-κB signalling pathways.

NF-κB Structure and Pathways

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

NF-κB was first described as a nuclear factor in B cells that binds the enhancer element controlling immunoglobulin κ light chain expression. Subsequently, NF-κB binding sites were identified in the promoter of a broad spectrum of genes which encode inflammatory cytokines and chemokines, major histocompatibility complex molecules, cell adhesion molecules, growth factors and regulators of apoptosis in various cell types [7]. Recognition of a variety of stimuli that include bacterial or viral antigens, cytokines and growth factors by members of the TNF receptor superfamily or toll-like receptors can activate NF-κB, leading to the production of inflammatory cytokines. In turn, inflammatory cytokines such as TNF-α and interleukin (IL)-1 activate NF-κB to enhance the inflammatory response [7]. NF-κB is composed of homo- and heterodimers of five members of the Rel family: NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), RelB and c-Rel [8]. The prototypical form of NF-κB is the heterodimeric p50/p65 complex. Under resting conditions, NF-κB homo- and heterodimers are sequestered in the cytoplasm in an inactive state by IκB proteins [8]. IκBs contain multiple copies of a 30–33-amino acid sequence, called ankyrin repeats, which mediate the association between IκBs and NF-κB dimers. The interaction between ankyrin repeats of IκB and the C-terminal region of NF-κB mask the nuclear localization sequence, thereby causing their cytoplasmic retention [8]. There are two distinct pathways of NF-κB activation, the canonical and the non-canonical pathway (Fig. 1). In the canonical pathway, IκBs are phosphorylated by upstream IKK complexes to induce their dissociation from NF-κB, followed by ubiquitination-dependent degradation of IκBs by 26S proteasomes. The released NF-κB complex is then able to translocate to the nucleus where it binds NF-κB consensus sites and regulates the expression of target genes in association with multiple co-activators and co-repressors [8]. The two catalytic IKK subunits, IKK-α and IKK-β, have canonical sequences that can be phosphorylated by upstream mitogen-activated protein kinase kinase kinases MEKK1-3, and NF-κB-inducing kinase [9]. IKK-γ, by contrast, has a regulatory role and the canonical NF-κB pathway is absolutely dependent on the integrity of IKK-γ. In the non-canonical pathway, IKK-α selectively phosphorylates the p100 precursor of the NF-κB p52 subunit in an IKK-β- and IKK-γ-independent manner, leading to nuclear translocation of p52/RelB heterodimers [9]. In innate immunity and inflammation, it seems that the canonical and the non-canonical pathways function as a coordinative system [9].

figure

Figure 1. Schematic representation of the NF-κB canonical and non-canonical pathways in regard to prostate cancer. P50-P65 is the major NF-κB dimer responsible for regulating transcriptional activation in the canonical pathway, but various combinations of the other subunits exist. TLR, toll-like receptor; TNF-R, tumour necrosis factor receptor; IκB, inhibitor of NF-κB; IKK, IκB kinase; NIK, NF-κB-inducing kinase; MEKK, MAP (mitogen-activated protein) kinase kinase kinase; AR, androgen receptor; BMDC, bone marrow-derived cell; MHC, major histocompatibility complex; p, phosphorylation.

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Constitutive Activation of NF-κB in PCa

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

The role of NF-κB in PCa is supported by data obtained from both human and in vitro and in vivo laboratory studies which have shown that NF-κB is aberrantly activated in the majority of PCa cases. Using various in vitro techniques such as electrophoretic mobility shift assay, chloramphenicol acetyltransferase (CAT) and β-galactosidase assay, RT-PCR and western blot analysis, several authors have demonstrated constitutive NF-κB nuclear activation and DNA-binding in PCa cell lines. More specifically, androgen-independent cell lines, such as PC-3 and DU-145, constitutively express high levels of NF-κB, while androgen-dependent cell lines, such as LNCaP and normal human prostate epithelial cells, have only low constitutive NF-κB activation [10]. Gasparian et al. [10] reported that constitutive complexes in PCa cell lines are represented by p65/p50 and p50/p50 dimers. Accordingly, when NF-κB is constitutively active or activated after exposure to stimuli, IKK-α is also active, IκB-α is strongly phosphorylated and rapidly degraded. Shukla et al. [11]evaluated NF-κB DNA-binding and the expression pattern of several NF-κB proteins in a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. They found increased DNA-binding of NF-κB/p65 and p50 in prostates of TRAMP mice during cancer progression in comparison with age-matched male littermates. Consistent with these findings, a time-dependent increase in the nuclear and cytosolic expression of NF-κB/p65, p50 and phosphorylated IκB-α was observed. De Angulo et al. [12] recently showed that T-cell function in aged mice (>22 months old) is characterized by increased cytokine production in comparison with young mice (6 weeks old). Furthermore, this aged T-cell response was able to induce NF-κB activation in PCa cells. These findings suggest that an aging immune system may play a role in PCa pathogenesis through elicitation of inflammatory signals.

A morphological basis for the existence of NF-κB activation in PCa is provided by immunohistochemical studies that reported positive staining for NF-κB proteins in PCa specimens [13, 14]. Accordingly, western blot analysis and electrophoretic mobility shift assays on PCa specimens showed increased levels of phosphorylated IκB-α and enhanced NF-κB DNA-binding, respectively, when compared with benign prostatic tissue [14]. Moreover, positive NF-κB staining was associated with a high Gleason score [14], biochemical recurrence [13] and shorter disease-specific survival [15] in univariate and multivariate models. Finally, nuclear NF-κB staining has also been detected in lymph node metastases, suggesting that NF-κB is linked to the metastatic phenotype [16].

Collectively, the available evidence confirms that NF-κB activation is a key event in PCa pathogenesis. Constitutive or induced activation of NF-κB may lead to amplification of the inflammatory response by providing a positive feedback signal to immune cells present in the tumour micro-environment, thereby increasing the production of molecular mediators which contribute to carcinogenic and inflammatory processes [17] (Fig. 2). In this regard, it seems that NF-κB activation is a late event in PCa development. Indeed, the presence of active NF-κB in normal prostate tissues at lower magnitude than in PCa is explained by the fact that NF-κB is a ubiquitous transcription factor which keeps a baseline activity to maintain essential physiological functions of all cells; however, levels of nuclear NF-κB gradually increase during transition from benign tissue to prostatic intraepithelial neoplasia, and from prostatic intraepithelial neoplasia to PCa [18], suggesting that NF-κB hyperactivation occurs once tumours are established.

figure

Figure 2. NF-κB is involved in prostate cancer (PC) progression to metastasis. Bone marrow-derived cells (BMDCs) are integral components of the tumour microenvironment. NF-κB pathways are activated in PC cells as well as in BMDCs, resulting in release of molecular mediators (Table 1) and positive feedback loops which contribute to processes needed for metastasis. In the bone microenvironment, activation of inflammatory signals in PC cells and maybe in BMDCs contributes to homing of cancer cells to the bone by stimulating osteoclast and osteoblast activity. Moreover, it has been shown that molecules such as IL-6 produced by osteoblasts can stimulate PC cell proliferation. EMT, epithelial-mesenchymal transition; TEM, transendothelial migration; ECM, extracellular matrix.

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NF-κB and Regulation of Apoptosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

Inhibition of the NF-κB pathway sensitizes PCa cells to apoptosis induced by various mediators [19]. An in vivo correlate of the in vitro data was provided by Xu et al. [20] They demonstrated that transfection of PC3 cells with dominant-negative p100 or siRNA targeting of RelB decreases RelB nuclear levels in vitro and delays tumour growth in selected clones inoculated into the flanks and prostates, respectively, of nude mice. Catz and Johnson [21]reported that NF-κB/p65 and p50 complexes bind the Bcl-2 promoter and that inhibition of NF-κB abates TNF-α-induced Bcl-2 expression in LNCaP cells, suggesting that the anti-apoptotic Bcl-2 protein is a downstream target of NF-κB in PCa. In another experiment, inhibition of the non-canonical NF-κB-pathway induced expression of the tumour suppressor maspin [22]. Other important downstream targets which are downregulated by NF-κB-inhibition in PCa include Bcl-xL, inhibitor of apoptosis 1 and 2 (IAP-1, IAP-2), cyclin D1 and lipocalin-2 [23, 24] (Table 1).

Table 1. Proposed target genes regulated by NF-κB in PCa
Tumour suppressor genesCell survival proliferationInvasion metastasisDrug resistance
  1. Mcl-1, induced myeloid leukemia cell differentiation protein; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; BMP, bone morphogenetic protein; uPA, urokinase plasminogen activator; ICAM1, intercellular cell adhesion molecule 1; VCAM1, vascular cell adhesion molecule 1; MDR1, multi-drug resistance protein 1.

p53 downregulationBcl-2 upregulationVEGF upregulationMDR1 upregulation
Rb downregulationMcl-1 upregulationIL-6 and -8 upregulation 
Maspin downregulationIAP-1 and -2 upregulationMMP-2 and -9 upregulation 
 Bcl-xL upregulation CXCL12-CXCR-4 upregulation 
 Caspase 3,6 and 7 downregulationCXCL1 and -2 upregulation 
 Cyclin D1-3 upregulationLipocalin-2 upregulation 
 Lipocalin-2 upregulationBMP upregulation 
 IL-1β upregulationuPA upregulation 
 IL-6 upregulationICAM1 upregulation 
 c-Myc upregulationVCAM1 upregulation 
  ESE1/ELF3 upregulation 

Altogether, these reports strongly support the hypothesis that NF-κB promotes cell survival through activation of anti-apoptotic molecules including Bcl-2 and IAP proteins. Most often, however, NF-κB inhibition alone is not sufficient to induce apoptosis [10, 25]. Indeed, parallel activation of other signalling pathways, such as the Fas cascade, appear necessary to achieve PCa cell apoptosis [25]. In this context, it is noteworthy that NF-κB activation in PCa cells can be induced by exposure to radiation [26] and chemotherapeutic agents including docetaxel [27]. This implies that in PCa cells NF-κB may be activated to evade the apoptotic effects of radiation and chemotherapy and thus contribute to the resistance of PCa to these therapies.

NF-κB and Metastatic PCa Phenotype

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

Several lines of evidence suggest that NF-κB activation is a key event in the acquisition of metastatic potential in PCa (Fig. 2). Huang et al. [28] showed that inhibition of NF-κB in highly metastatic PC3 cells decreases invasion through Matrigel® in vitro and inhibits tumour growth, angiogenesis and occurrence of lymph node metastasis in orthotopic nude mouse models. Furthermore, NF-κB inhibition was associated with the downregulation of pro-invasive molecules including vascular endothelial growth factor, IL-8 and matrix metalloproteinase-9. NF-κB promotion of PCa may also involve the regulation of transendothelial migration, a crucial step within the metastatic cascade. Indeed, Kukreja et al. [29] reported that overexpression of NF-κB increases NF-κB-dependent activation of the CXCL12/CXCR4 chemokine pathway and consequently PCa cell adhesion to endothelial cells and transendothelial migration, an effect that was reversed by the mutant IκB-α super-repressor. The CXCL12/CXCR4 pathway has been implicated in PCa metastasis to bone [30]. Similarly, the pro-inflammatory cytokines CXCL-1 and -2 have been associated with the establishment of lung metastases through a feedback loop involving NF-κB in PCa xenograft models [31]. Furthermore, Longoni et al. [32] recently revealed a positive feedback loop between NF-κB and the ETS transcription factor ESE1/ELF3. This feedback loop maintained NF-κB activation and was associated with tumour growth and metastatic spread in PCa xenografts, as well as poor prognosis in human prostate tumours. At the same time, genome-wide transcriptome profiling showed that ESE1/ELF3 overexpression induced genes involved in the inflammatory response, further supporting the link between inflammation and PCa [32]. The metastasic process is also characterized by epithelial to mesenchymal transition, during which tumour cells lose their epithelial features and acquire mesenchymal characteristics and invasive properties. Baritaki et al. [33] showed that inhibition of NF-κB confers DU-145 cells with a more epithelial phenotype and most importantly, suppresses Snail-dependent migration and invasion. Andela et al. [34] reported that bone resorption, a key event in the successful establishment of osteoblastic metastases, is abrogated when mutant PC-3 cells lacking NF-κB function are co-cultured with rat bone marrow cells on bone slices. Moreover, NF-κB inactivation in PC-3 cells has been found to inhibit tumour establishment and growth in bone in vivo, while NF-κB activation in the LNCaP cell line had the opposite effect [35]. One way by which NF-κB promotes metastasis may be partly by regulating transcription and activation of bone morphogenetic proteins [36]. Bone morphogenetic proteins are members of the TGF-β superfamily which have been involved in the formation of bone metastases in PCa [36]. Taken together, the available evidence supports the model that intrinsic NF-κB activation may promote the metastatic phenotype in PCa through regulation of genes involved in cell invasion and adhesion, angiogenesis and homing of cancer cells to bone.

NF-κB and PCa Progression to Castration-resistant Prostate Cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

We have mentioned above that androgen-independent cell lines constitutively express high levels of NF-κB, while androgen-dependent cell lines do not [10]. NF-κB expression is upregulated in patients with castration-resistant prostate cancer (CRPC) who progress more rapidly [15]. It has been suggested that interference exists between NF-κB and the androgen receptor (AR) and that their activity is mutually exclusive [37]; however, conflicting reports have been published. For instance, NF-κB nuclear translocation is decreased by AR expression in PC-3 cells, and diminished further by dihydrotestosterone [37], while NF-κB subunits are capable of inhibiting AR transcriptional activity in LNCaP cells, which have a functional AR [38]. These observations suggest that in the androgen-dependent state NF-κB activity may be repressed by an active AR, and that upon transition to CRPC, NF-κB activation occurs as AR loses ligand-dependent activity. Conversely, NF-κB may be responsible for accessory activation of the AR during transition to CRPC. The latter is characterized by cell alterations such as AR amplification, AR mutation, dysregulation of AR coregulatory proteins and growth factors that can activate the AR in a ligand-independent manner [39]. In this regard, Jin et al. [40] showed that NF-κB activates transcriptional activity of the AR in LNCaP cells. In addition, continuous NF-κB activation maintained high levels of nuclear AR in vivo and, most importantly, prevented regression of the prostate after castration [40]. Recently, Zhang et al. [41] showed that p65 or the combination of p65/p50 upregulates AR expression in LNCaP cells, while NF-κB/p50 has a slight inhibitory effect. Along the same line, overexpression of p52 has the capacity to activate the AR under low-androgen conditions [42] and to induce tumour growth in castrated LNCaP xenograft models [43]. Interestingly, Suh et al. [44]showed that the AR seems to have dual effects on NF-κB activation depending on the availability of androgens; therefore, the balance of androgens, NF-κB subunit complexes, stimuli and cofactors regulating the NF-κB pathway during transition to CRPC may determine the overall effect of NF-κB on AR activity, and vice versa.

Collectively, a paradigm emerges from these studies that NF-κB activation controls PCa transition to CRPC after androgen withdrawal, possibly through the regulation of AR activity.

NF-κB and a Novel Nuclear Role for IKK-α

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

Recently, another mechanistic link between inflammation and cancer has been delineated by studies from Michael Karin's group. In the first paper, Luo et al. [45] reported that TRAMP mouse models with a mutated IKK-α exhibit fewer metastases than do wild-type TRAMP mice. During PCa progression, expression of maspin remained high in IKK-α-mutated TRAMP mice, while it was suppressed in wild-type IKK-α models. IKK-α appeared to control and repress maspin expression at the promoter level. In the next set of experiments, levels of active nuclear IKK-α correlated with PCa progression and reduced expression of maspin in wild-type IKK-α mice as well as in human PCa specimens at different tumour stages. Furthermore, it was demonstrated that only activated IKK-α-transduced primary PCa cells show metastatic activity. Most importantly, the authors observed a vast increase in tumour infiltrating T cells and macrophages in PCa of older mice. At the same time, higher expression of RANKL, a known IKK-α activator, was detected. Treating primary PCa cells with RANKL resulted in decreased maspin expression in wild-type TRAMP cells, while no effect was seen in IKK-α-mutated mice.

In a second paper, Ammirante et al. [46] showed that deletion of IKK-β in prostate epithelial cells of TRAMP mice has no effect on the genesis and progression of PCa, while absence of IKK-β in bone marrow-derived cells delays the emergence of CRPC after castration. At the same time, they noted that hormone deprivation provokes infiltration of regressing tumours with leukocytes, including B cells, in the prostate of allograft models after castration. Moreover, the authors demonstrated that nuclear activation of IKK-α in castrated PCa allografts is dependent on IKK-β in bone marrow-derived cells and on B cells. It was found that one important molecule involved in PCa progression to CRPC is the cytokine lymphotoxin in B cells, whose expression in B cells was abolished by deletion of IKK-β. A subsequent study investigating the molecular mechanisms underlying IKK-α enhancement of cell survival and proliferation reported that IKK-α is able to activate the transcription factor E2F1 and its downstream target Bmi1 in prostate stem cell/progenitor cells [47]. These findings suggest that expansion of PCa progenitors by IKK-α occurs during disease progression to CRPC. It was previously shown that from the two IKK catalytic subunits, IKK-α is predominant in PCa [11].

Together these recent studies have validated the crucial role played by inflammatory cells and IKK-α during PCa progression. Most importantly, they show that the course of PCa to the castration-resistant metastatic phenotype is associated with a concurrent increase in tumour-infiltrating leukocytes. These lymphoid and myeloid cells which have been recruited may secrete mediators which activate an NF-κB-independent IKK-α-pathway and thereby promote metastasis and progression to CRPC.

Targeting the NF-κB Pathway

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

NF-κB activation in PCa cells can be induced by exposure to radiation [26] and chemotherapeutic agents [27], suggesting that NF-κB may have a protective effect and contribute to resistance of PCa to conventional therapy. It follows that NF-κB inhibition sensitizes PCa cells to the apoptotic effects of radiation and chemotherapy [27]; therefore, attempts have been made to target the NF-κB pathway alone and in combination with conventional agents. Bortezomib inhibits the proteasome, a multiprotein complex that degrades the majority of intracellular proteins and thus regulates physiological and pathological cellular processes [48]. Inhibition of the ubiquitin-proteasome pathway may prevent NF-κB activation through stabilization of IκB-α activity, which would otherwise be degraded after exposure to genotoxic stress [48]. Bortezomib has become a cornerstone of diverse therapeutic regimens in multiple myeloma [49] and has shown antitumour effects against PCa cells in vitro and in vivo [50]. Several phase II trials investigating bortezomib alone and with prednisone or docetaxel in patients with CRPC have, however, failed to show antitumour effects [51] or have presented results which were in the range of what would be expected with docetaxel alone [52]. More encouragingly, in another phase II trial the authors reported a statistically significant stabilization of serum PSA levels in patients with biochemical recurrence after definitive local therapy for PCa treated with bortezomib alone before androgen deprivation [53]. One possible explanation of bortezomib failure in PCa might be the fact that at doses required for tumour apoptosis, significant side effects would occur. Direct targeting of NF-κB molecules or targeting of the non-canonical pathway may be more advantageous [20]. One emerging area of interest is the possibility of combining bortezomib with novel targeted agents that include histone deacetylase inhibitors, kinase inhibitors and monoclonal antibodies [54]. Translational research and early clinical trials are currently underway to help validate this therapeutic strategy in various haematological and solid tumours, including PCa [54]. In 2012, a second generation proteasome inhibitor, carfilzomib, was approved by the US Food and Drug Administration for the treatment of patients with multiple myeloma who have failed bortezomib therapy [49]. Recently, two novel proteasome inhibitors, marizomib (NPI-0052) and ixazomib (MLN9708), were shown to inhibit PCa progression in vitro and in vivo [33, 55]. More than 20 clinical trials evaluating these compounds in patients with multiple myeloma or solid tumours are underway (http://www.clinicaltrials.gov). Another effective approach for inhibition of NF-κB activation may be offered by specific inhibition of the IKK complex. The IKK-inhibitor PS1145 has demonstrated the ability to cause apoptosis and inhibit invasion of PCa cells in vitro [24]. Another IKK-inhibitor, BMS345541, was shown to reduce proliferation in AR-expressing PCa cell lines. This effect was accompanied by a reduction in AR activity [56]. To date, however, none of these agents has received clinical approval and further development is warranted.

Collectively, these reports underscore the need to refine agents targeting NF-κB signalling pathways. In this regard, it may be important to implement inflammatory markers or imaging technologies which could help identify the best candidates for such therapies, particularly in light of the heterogeneous nature of PCa.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

In summary, the evidence presented in this review provides a critical connection between inflammation and PCa. NF-κB, the master transcription factor in inflammatory responses, is a key mediator in several steps of PCa pathogenesis, including protection against apoptosis, induction of metastastic phenotype and PCa progression to CRPC. We are, however, only at the beginning of understanding the role of inflammatory cells in the tumour micro-environment. Further research designed to dissect the mechanistic pathways involved in inflammation and PCa is thus warranted in order to design appropriate preventive measures and more efficient therapeutic strategies in PCa.

Conflict of Interest/Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References

D.P.N is a Visiting Fellow and is supported by research grants from the Nuovo-Soldati, the Arnold U. and Susanne Huggenberger-Bischoff, the Swiss Urological Association and the Bangerter Foundations (Switzerland).

J.L has no conflict/acknowledgement to declare. S.S.Y. is a Research Associate and Prostate Cancer Foundation Young Investigator. A.K.T. is the principal investigator on research grants from Intuitive Surgical, Inc. and Boston Scientific Corporation. He is a non-compensated director of Prostate Cancer Institute (Pune, India) and Global Prostate Cancer Research Foundation. He has received research funding from the LeFrak Family Foundation, Mr and Mrs Paul Kanavos, Craig Effron and Co., the Charles Evans Foundation and Christian and Heidi Family Foundation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. NF-κB Structure and Pathways
  5. Constitutive Activation of NF-κB in PCa
  6. NF-κB and Regulation of Apoptosis
  7. NF-κB and Metastatic PCa Phenotype
  8. NF-κB and PCa Progression to Castration-resistant Prostate Cancer
  9. NF-κB and a Novel Nuclear Role for IKK-α
  10. Targeting the NF-κB Pathway
  11. Conclusion
  12. Conflict of Interest/Acknowledgements
  13. References
Abbreviations
CRPC

castration-resistant prostate cancer

IκB

inhibitor of NF-κB

IKK

inhibitor of NF-κB kinase

PCa

prostate cancer

IL

interleukin

TRAMP

transgenic adenocarcinoma of the mouse prostate

IAP

inhibitor of apoptosis

AR

androgen receptor